Biological and lifestyle factors contributing to Tau in women at risk for Alzheimer's disease.

在有阿尔茨海默病风险的女性中，生物和生活方式因素会导致 Tau 蛋白的形成。

• 批准号: 10591159
• 负责人: SARAH BANKS
• 金额: $ 102.59万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10591159
• 关键词: Acceleration; Address; Adverse effects; Alzheimer' s Disease; Alzheimer' s Disease Pathway; Alzheimer' s disease pathology; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Anti-Inflammatory Agents; Autoimmune Diseases; Biological; Biological Assay; Biological Factors; Brain; Central Nervous System; Cerebrospinal Fluid; Cognition; Cognitive; Cognitive deficits; Data; Data Collection; Dementia; Disease; Disease Outcome; Elderly; Endocrine; Enrollment; Female; Funding; Genetic; Genetic Risk; Gonadal Steroid Hormones; Health; Hormones; Immune; Immune response; Impaired cognition; Individual; Inflammation; Inflammatory; Inflammatory Response; Interleukin-6; Intervention; Investigation; Joints; Knowledge; Life Style; Life Style Modification; Link; Measures; Mediating; Memory; Menopause; Modeling; Observational Study; Obstructive Sleep Apnea; Outcome; Participant; Pathogenesis; Pathologic; Pathology; Pathway interactions; Performance; Physical activity; Physical assessment; Pilot Projects; Play; Positron-Emission Tomography; Predisposition; Proteins; Receptors, Tumor Necrosis Factor, Type II; Reporting; Reproductive History; Research Priority; Risk Factors; Risk Reduction; Role; Sample Size; Sampling; Severities; Sex Differences; Sleep; Stress; Symptoms; TNF gene; TNFRSF1B gene; Testosterone; Time; Tumor Markers; United States National Institutes of Health; Woman; Work; associated symptom; cognitive function; cytokine; diet and exercise; experience; follow up assessment; improved; lifestyle factors; lifestyle intervention; men; mild cognitive impairment; modifiable risk; neuroimaging; neuroinflammation; older women; pharmacologic; receptor; recruit; sedentary lifestyle; sex; sex disparity; tau Proteins; tau aggregation; tau function; tau-1; therapeutic target

PROJECT SUMMARY/ABSTRACT Growing evidence reports that women show a more aggressive profile of Alzheimer's disease (AD) than men with greater pathological tau burden and steeper cognitive decline; yet the reasons for these sex differences are poorly understood. Sex differences in AD point to sex-disparate causal pathways as well as sex-specific therapeutic targets. Neuroinflammation (N-Inf) is one candidate casual pathway that shows sex disparities and plays a central role in AD pathogenesis with close ties to both tau and cognitive decline. Women tend to have a more robust immune/inflammatory response and comprise 80% of autoimmune disease cases. Moreover, our own preliminary work in the Alzheimer's Disease Neuroimaging Initiative indicated that women may be more susceptible than men to the adverse effect of N-Inf, particularly the markers of TNFα, IL6 and their receptors on cerebrospinal fluid (CSF) levels of phosphorylated tau (p-tau) and cognitive function. There are also lifestyle factors such as physical activity and obstructive sleep apnea (OSA) known to influence N- Inf and relate to tau and cognitive decline and to do so differently in women versus men. Our own preliminary data highlight sedentary behavior and obstructive sleep apnea as two modifiable risk factors that show strong associations with N-Inf, tau and/or cognitive function in older women, and thus stress the need to further understand how and to what degree these lifestyle interventions could reduce AD risk. Together, these findings led us to this proposed observational study that will examine how N-Inf markers (specifically TNFα, TNFR2, IL6 and IL6R) and the modifiable risk factors that influence N-Inf relate to tau accumulation and cognitive decline in older women at-risk for AD by way of mild cognitive deficits and genetic risk. Moreover, we will explore how sex hormones, particularly testosterone, contribute to these relationships given their anti-inflammatory and central nervous system effects and often contributing role to sex differences. To achieve this, we propose to measure CSF N-Inf markers, physical activity, OSA, and circulating sex hormones in a sample of 100 older women at-risk for AD and relate these measures to changes in cognitive function and accumulation of tau, measured via positron emission tomography (PET), over a two-year period. This study will build upon a state-funded, pilot study by increasing the sample size and adding longitudinal assessments in order to conduct a rigorous examination of our hypotheses. In keeping with NIH research priorities, after 5 years of potential funding, this project will help to close critical gaps in our understanding of sex differences in AD by examining under-explored yet highly-relevant mechanisms that may contribute to the greater pathology and steeper cognitive decline in women on the AD trajectory. Furthermore, our findings will inform risk reduction strategies that influence these mechanisms – an important focus given current the lack of disease-modifying treatments.

越来越多的证据表明，女性表现出更积极的个人形象， 阿尔茨海默病（AD）的发病率高于男性，病理性tau蛋白负荷更大，认知能力下降更严重;然而， 对这些性别差异的原因知之甚少。AD的性别差异表明性别差异的因果关系 途径以及性别特异性治疗靶点。神经炎症（N-Inf）是一个候选的因果通路 这显示了性别差异，并在AD发病机制中起着核心作用，与tau蛋白和认知功能密切相关。 下降女性往往有更强大的免疫/炎症反应，占自身免疫性疾病的80%。 疾病病例。此外，我们自己在阿尔茨海默病神经成像倡议中的初步工作表明， 女性可能比男性更容易受到N-Inf的不良影响，特别是TNFα标志物， IL 6及其受体对脑脊液（CSF）磷酸化tau（p-tau）水平和认知功能的影响。 还有一些生活方式因素，如身体活动和阻塞性睡眠呼吸暂停（OSA），已知会影响N- 与tau蛋白和认知能力下降有关，并在女性和男性中以不同的方式进行。我们自己的初步数据 强调久坐行为和阻塞性睡眠呼吸暂停是两个可改变的风险因素， 与N-Inf，tau和/或老年妇女的认知功能相关，因此强调需要进一步 了解这些生活方式干预如何以及在多大程度上可以降低AD风险。总之，这些发现 引导我们进行这项观察性研究，研究N-Inf标志物（特别是TNFα、TNFR 2、IL 6） 和IL 6 R）和影响N-Inf的可改变的风险因素与tau蛋白积累和认知能力下降有关， 老年妇女有轻度认知缺陷和遗传风险的AD风险。此外，我们将探讨性如何 激素，特别是睾酮，有助于这些关系，因为它们具有抗炎和中枢神经系统功能。 神经系统的影响，并往往有助于性别差异的作用。为了实现这一目标，我们建议 100例高危老年女性的CSF N-Inf标记物、体力活动、OSA和循环性激素 并将这些测量与认知功能的变化和tau的积累相关，通过 正电子发射断层扫描（PET），为期两年。这项研究将建立在一个国家资助的试点， 研究通过增加样本量和增加纵向评估，以进行严格的 检查我们的假设。为了与NIH的研究重点保持一致，经过5年的潜在资助， 该项目将有助于缩小我们对AD性别差异理解的关键差距， 然而，高度相关的机制，可能有助于更大的病理和陡峭的认知下降， 在AD轨迹上的女性。此外，我们的研究结果将为影响这些风险的风险降低策略提供信息。 机制-一个重要的焦点，鉴于目前缺乏疾病修饰治疗。